Maria L. Melzi

Split-liver transplantation eliminates the need for living-donor liver transplantation in children with end-stage cholestatic liver disease.

Background. End-stage cholestatic liver disease (ESCLD) is the main indication for liver replacement in children. Pediatric cadaver–organ-donor shortage has prompted the most important evolutions in the technique of liver transplantation, in particular living-donor liver transplantation (LDLT) and split-liver transplantation (SLT). Methods. Between November 1997 and June 2001, 127 children with ESCLD were evaluated for liver transplantation, and 124 underwent 138 liver transplantations after a median time of 40 days. Causes of liver disease were congenital biliary atresia (n=96), Alagille’s syndrome (n=12), Byler’s disease (n=8), and other cholestatic diseases (n=8). Results. Ninety (73%) patients received a split-liver graft, 28 (23%) a whole liver, and 6 (4%) a reduced-size liver. Overall 2- and 4-year patient survival rates were 93% and 91%, respectively; the 2- and 4-year graft-survival rates were 84% and 80%, respectively. In split-liver recipients, 4-year patient and graft-survival rates were 91% and 83%, respectively; these were 93% and 78%, respectively, in whole-liver recipients and 67% and 63%, respectively, in reduced-size liver recipients. Retransplantation rate was 11%, whereas mortality rate was 8%. Overall incidence of vascular and biliary complication were 16% and 27%, respectively. Conclusions. SLT can provide liver grafts for children with ESCLD with an outcome similar to the one reported following LDLT, eliminating mortality while they are on a transplantation wait list. The need for pediatric LDLT should be reevaluated and programs of SLT strongly encouraged and supported at a national and international level.

Liver transplant in cystic fibrosis: a poll among European centers. A study from the European Liver Transplant Registry

Liver Transplant (LTx) has been rarely performed in cystic fibrosis (CF) patients and indications and outcomes are not well defined. A questionnaire was sent to all European CF and LTx centers to collect data on CF transplanted patients. We obtained information regarding 57 CF patients. LTx has been performed prevalently in males and in pediatric age. The main complication of cirrhosis was portal hypertension with hypersplenism. In the majority of cases the decision to transplant was based on the contemporary presence of various factors. Post‐LTx survival was high and comparable with that expected for more common pediatric LTx indications. Poor respiratory function was the main risk factor for early death. In the short‐term, respiratory function significantly improved after LTx. LTx is the appropriate treatment for patients with advanced CF‐related liver disease and preserved pulmonary function (Forced Expiratory Volume at 1u2003s, FEV1 >50%). This poll reveals that most European liver centers perform LTx prior to the development of end‐stage liver disease or overt pulmonary or other clinical decompensation.

Late graft dysfunction and autoantibodies after liver transplantation in children: preliminary results of an Italian experience.

Late graft dysfunction (GD) associated with the development of autoantibodies is a common event after pediatric liver transplantation (OLTx) and can present in 2 clinicohistological subsets: de novo autoimmune hepatitis (DNAH) and early chronic rejection (ECR). Sixty out of 247 children developed autoantibodies after OLTx. GD was demonstrated in 22 (37%); based on histology, patients were divided in a DNAH and an ECR group. Portal/periportal inflammatory infiltrate with interface/lobular hepatitis was suggestive for DNAH. Pericentral hepatocytes confluent dropout with a variable degree of central vein endothelitis, but not with ductopenia (loss of >50% of interlobular bile ducts), was diagnosed as ECR. Nine patients had DNAH and 13 ECR. Five out of 9 in the DNAH group were on cyclosporin (CsA) and 4/9 were on tacrolimus (Tac). In the ECR group, 11 children were treated with CsA and 2 with Tac. All DNAH patients had normal liver function tests on steroids and azathioprine (AZA). Five patients with ECR recovered by increasing calcineurin inhibitors (CNIs) dosage, but in 8/13, including 7 switched from CsA to Tac, AZA and steroids were added to obtain remission of disease. Two patients developed late chronic rejection. DNAH and ECR associated with autoantibodies are forms of late GD after OLTx. DNAH improves after standard treatment of autoimmune hepatitis. ECR has a good response to increased doses of CNIs, although ductopenic chronic rejection may occur. In conclusion, the early differential diagnosis of these conditions and an appropriate treatment seem to allow good overall results reflected by a graft survival of more than 90%. Liver Transpl 12:573–577, 2006.

Sensenbrenner syndrome: A new member of the hepatorenal fibrocystic family

Cranioectodermal dysplasia (CED, Sensenbrenner syndrome; OMIM #218330) is an autosomal recessive disorder reported only in 15 cases, which is characterized by dolichocephaly, rhizomelic dwarfism, dental and nail dysplasia, and progressive tubulo‐interstitial nephritis (TIN) leading to end‐stage renal failure. Herein, we describe a new patient with cranio‐ectodermal dysplasia. Unlike previously reported cases, this 4‐year‐old child presented with tubulo‐interstitial nephropathy associated with liver cystic disease and elevated liver enzymes. The liver biopsy demonstrated congenital hepatic fibrosis secondary to ductal plate malformation. The coexistence of a chronic tubulo‐interstitial renal disease with lesions associated to malformations of the hepatic ductal plate indicates that CED as a new member of the congenital hepatorenal fibrocystic syndromes.

Delayed intestinal visualization at hepatobiliary scintigraphy is associated with response to long-term treatment with ursodeoxycholic acid in patients with cystic fibrosis-associated liver disease

BACKGROUND/AIMSnAbnormalities of biliary drainage have been documented at hepatobiliary scintigraphy in many but not all patients studied with cystic fibrosis-associated liver disease. Ursodeoxycholic acid was shown to be beneficial in this disease, mainly by improving biliary secretion. Therefore, patients with impaired biliary drainage are expected to obtain the greatest benefit from this treatment.nnnMETHODSnWe evaluated the effects of long-term treatment with ursodeoxycholic acid in 36 patients with cystic fibrosis-associated liver disease, and compared the response in patients presenting a normal (n=18) or delayed time of intestinal visualization (n=18) at baseline hepatobiliary scintigraphy.nnnRESULTSnThe mean treatment duration was 58+/-26 (S.D.) months and 63+/-29 months in the groups with normal or delayed time of intestinal visualization, respectively. The time of intestinal visualization decreased (57+/-23%, p<0.001) from baseline in patients with initially abnormal values and became normal in four (22%). Treatment failure, i.e. lack of sustained normalization of serum liver enzymes or the occurrence of a clinically relevant adverse event, was more frequently observed in patients with a normal time of intestinal visualization at baseline (OR, 5.50; 95% CI, 1.32-22.7). When only clinically relevant adverse events were considered, they occurred in six of the latter patients (liver transplantation in one case, development of ultrasographic or endoscopic signs of portal hypertension in six cases), but in only one patient (development of portal hypertension) in the group with delayed time of intestinal visualization (OR, 10.82; 95% CI, 1.17-100.4).nnnCONCLUSIONSnDelayed intestinal visualization at hepatobiliary scintigraphy in patients with cystic fibrosis-associated liver disease seems to predict a better response to ursodeoxycholic acid.

Combined double lung-liver transplantation for cystic fibrosis without cardio-pulmonary by-pass.

Sequential bilateral single lung‐liver transplantation (SBSL‐LTx) is a therapeutic option for patients with end stage lung and liver disease (ESLLD) due to cystic fibrosis (CF). A few cases have been reported, all of them were performed with the use of cardio‐pulmonary by‐pass (CPB). We performed SBSL‐LTx in three young men affected by CF. All the recipients had respiratory failure and portal hypertension with hypersplenism. Along with lung transplants, two patients received a whole liver graft and one an extended right graft from an in situ split liver. During transplantation neither CPB nor veno‐venous by‐pass (VVB) were employed. Immunosuppression was based on basiliximab, tacrolimus, steroids and azathioprine. The three recipients are alive with a median follow‐up of 670 days (range 244–1533). Combined SBSL‐LTx is a complex but effective procedure for the treatment of ESLLD due to CF, not necessarily requiring the use of CPB or VVB.

Specific autologous cytotoxic T lymphocytes for chronic varicella in a liver transplanted child.

Abstract:u2002 Infections by herpesviruses may have severe complications in liver transplant patients. Although prophylactic varicella zoster virus vaccination is strongly recommended and widely applied, severe infection may still occur. We report the case of systemic chronic varicella, which developed in a liver allograft recipient, unresponsive to antiviral drug treatment, successfully treated by varicella zooster‐specific CTL. Graft failure ensued, likely, because of massive cytolysis of infected hepatocytes. The patient, who was re‐transplanted in the absence of signs of varicella zooster reactivation, is now well and disease free 3u2003yr after second liver transplant.

Plasma oxysterols in normal and cholestatic children as indicators of the two pathways of bile acid synthesis

BACKGROUNDnNo information is available on the hepatic and extrahepatic pathways of bile acid synthesis in normal children and in pediatric cholestatic liver diseases.nnnMETHODSnTo explore the changes of the two pathways of bile acid synthesis during development, plasma concentrations of 7alpha-hydroxycholesterol and 27-hydroxycholesterol were measured in 50 healthy children (1 month-14 years) and compared to 18 adult controls. We also measured plasma oxysterols in 31 patients with pediatric cholestatic liver disease.nnnRESULTSnA progressive increase of plasma concentrations of both 27-hydroxycholesterol and 7alpha-hydroxycholesterol was found with age. In children with cystic fibrosis-associated liver disease plasma concentrations of 27-hydroxycholesterol were significantly lower compared to age-matched controls (5.6+/-0.5 vs. 12.8+/-1.1 microg/dl; p<0.001) and paralleled significantly lower concentrations of total cholesterol. In infants with biliary atresia plasma concentrations of 27-hydroxycholesterol were significantly higher compared to age-matched controls (8.8+/-0.8 vs. 4.4+/-0.6 microg/dl, p<0.001) paralleling significantly higher concentrations of total cholesterol while 7alpha-hydroxycholesterol resulted significantly lower (1.2+/-0.2 vs. 2.3+/-0.3 microg/100 mg of total cholesterol; p=0.011).nnnCONCLUSIONSnOur data suggest that both pathways of bile acid synthesis reach a state of maturity only after the age of 4 years and are significantly influenced also in children by liver function and intestinal absorption of cholesterol.

A Randomized Trial For Tacrolimus And Steroids Vs. Tacrolimus And Basiliximab In Pediatric Liver Transplantation

Aims: Basiliximab is a monoclonal antibody against IL-2 receptor. A comparison between immunosuppression carried out with Tacrolimus (TAC) and Steroids (ST) VS. Tacrolimus and Basiliximab (BAS) was performed to evaluate the efficiency and safety of these two drugs association after pediatric liver transplantation. Methods: A randomized prospective trial was started in June 2001 at the Liver Transplantation Center in Bergamo, Italy. Patients receiving primary liver transplantation were enrolled in two groups: group A (TAC ST) or in group B (TAC BAS). A total of 64 patients were recruited in the study, 32 in group A and 32 in group B. Mean age was 3 yrs (0.5-16.9) and mean weight was 13.3 (4-65). The main indication for transplantation was biliary atresia. Primary endpoint of the study was the incidence of acute rejection (ACR) in the first three months. Secondary endpoints of the study were the cumulative incidence and severity of ACR, patient and graft survival, and incidence of adverse events. Tacrolimus was given at an initial dose of 0.08 mg/kg/die and then adjusted to obtain trough levels between 10 and 15 ng/ml during the first three months and of 5/10 ng/ml after the 3 month. ST were administered at the dose of 2 mg/kg and tapered before being stopped after three months. BAS was given at the dose of 20 mg iv on postoperative day 0 and 4. Results: Overall survival rate was 92%, 93% for patients in group A and 90% for patients in group B. 4 patients were excluded from the study (1 in group A and 3 in group B) for early death or discontinuation of immunosuppression. Rejection episodes were 7 in group A (22%) and 2 in group B (7%). Mean RAI score was 6 for group A, while the two patients in group B had a RAI of 4. Rejection occurred after 11 days (mean) in group A and after 20 and 223 days in the two cases in group B. One patient in group B had PTLD. Rates of EBV seroconversion were respectively (group A vs. group B) 25% and 17%. CMV infection rates were 19% vs. 13%. Sepsis occurred in 25% of patients in group A vs. 13% in group B. Conclusions: ACR seems to be less frequent in the BAS group and, even when it occurs, shows a delayed onset and a less severity. Severe infectious episodes are more rare without the use of steroids. Adverse effects of BAS were not observed in this study. Long term follow-up needs to clarify the effect of these results on the occurrence rate of late complications and chronic rejection.

ORTHOTOPIC LIVER TRANSPLANTATION FOR BYLER’S DISEASE

In this study we analyzed the features of 12 patients who underwent liver transplantation for progressive familial intrahepatic cholestasis (Bylers disease [BD]) in view of the technical features of the OLTx, incidence and type of complications, need for retransplantation, as well as patient and graft survivals. BD was the indication in 12 patients of median age 1.32 years and median weight 10 kg. Median follow-up was 670 days. Major surgical complications requiring reintervention occurred in three patients. No thrombosis of the hepatic artery was observed. Infections with positive blood cultures were diagnosed in four patients. One patient had a biliary anastomotic stenosis successfully treated by percutaneous techniques. Four patients had episodes of acute rejection treated with steroids. Two patients were retransplanted, both of whom died in the early postoperative period due to hepatic vein thrombosis and venoenteric fistula. The actuarial patient and graft survival was 83% at 1 year and 83% at 5 years. Split-liver grafts represent an excellent organ supply for these patients, achieving good results with no mortality on the waiting list.